Disparate Effects of Diabetes and Hyperlipidemia on Experimental Kidney Disease

Abstract

It is well established that diabetes is the major cause of chronic kidney disease worldwide. Both hyperglycemia, and more recently, advanced glycation endproducts, have been shown to play critical roles in the development of kidney disease. Moreover, the renin-angiotensin system along with growth factors and cytokines have also been shown to contribute to the onset and progression of diabetic kidney disease; however, the role of lipids in this context is poorly characterized. The current study aimed to compare the effect of 20 weeks of streptozotocin-induced diabetes or western diet feeding on kidney disease in two different mouse strains, C57BL/6 mice and hyperlipidemic apolipoprotein (apo) E knockout (KO) mice. Mice were fed a chow diet (control), a western diet (21% fat, 0.15% cholesterol) or were induced with streptozotocin-diabetes (55 mg/kg/day for 5 days) then fed a chow diet and followed for 20 weeks. The induction of diabetes was associated with a 3-fold elevation in glycated hemoglobin and an increase in kidney to body weight ratio regardless of strain (p < 0.0001). ApoE deficiency significantly increased plasma cholesterol and triglyceride levels and feeding of a western diet exacerbated these effects. Despite this, urinary albumin excretion (UAE) was elevated in diabetic mice to a similar extent in both strains (p < 0.0001) but no effect was seen with a western diet in either strain. Diabetes was also associated with extracellular matrix accumulation in both strains, and western diet feeding to a lesser extent in apoE KO mice. Consistent with this, an increase in renal mRNA expression of the fibrotic marker, fibronectin, was observed in diabetic C57BL/6 mice (p < 0.0001). In summary, these studies demonstrate disparate effects of diabetes and hyperlipidemia on kidney injury, with features of the diabetic milieu other than lipids suggested to play a more prominent role in driving renal pathology.

Risk Factors and Comorbidities Associated with Diabetic Kidney Disease

“…20 Hyperlipidemia has been implicated in the pathogenesis of DKD, however experimental models show that elevated levels of total cholesterol and triglycerides were not sufficient to drive overt changes in renal structure and function. 37 On the contrary, prospective cohort study of type-2 DM patients for a median period of 5.8 years showed that elevated total cholesterol levels were associated with increased risk for the development of both moderate and severe increase in the UACR. 15 Similarly, Samsu 38 reported in a review that low levels of total cholesterol and triglycerides were associated with regression from moderate albuminuria to normal UACR.…”

Aerobic exercise training combined or not with okra consumption as a strategy to prevent kidney changes caused by metabolic syndrome in Zucker rats

“…Dyslipidemia is found in most patients with CKD, even in the early stages and is related to the decline in renal function [ 40 , 41 ]. Previous data demonstrated that hyperlipidemia was slightly associated with renal pathology and that the increase in plasma lipids alone was not sufficient to cause significant renal damage [ 42 ]. It was also reported that the more severe the diabetes, the more severe the renal dysfunction [ 42 ].…”

“…Previous data demonstrated that hyperlipidemia was slightly associated with renal pathology and that the increase in plasma lipids alone was not sufficient to cause significant renal damage [ 42 ]. It was also reported that the more severe the diabetes, the more severe the renal dysfunction [ 42 ]. In fact, hyperglycemia is associated with CKD development [ 43 ], which can promote changes in renal function [ 5 ].…”

The Relationship between Renin–Angiotensin–Aldosterone System (RAAS) Activity, Osteoporosis and Estrogen Deficiency in Type 2 Diabetes

“…Furthermore, Ang II-based activation of AT1R causes insulin resistance by increasing hepatic triglyceride levels, which is thought to contribute to the development of diabetes [28,43]. Diabetic dyslipidemia is associated with damage to vital organs such as the heart and kidneys [44,45]. Local RAAS in the kidneys has been evidenced, in various studies, to cause morphological changes that affect kidney function [44,46].…”

“…Diabetic dyslipidemia is associated with damage to vital organs such as the heart and kidneys [44,45]. Local RAAS in the kidneys has been evidenced, in various studies, to cause morphological changes that affect kidney function [44,46]. In T2D, systemic and kidney RAAS have been positively correlated with proteinuria and hypertension [46,47].…”